Long Term Goals: Serenix Pharmaceuticals (SP) will develop drugs to treat impulsivity, violence, and self-injurious behavior in patients with autism, Tourette's syndrome, and mental retardation. These drugs, termed serenics, stop violent behavior without disrupting normal behaviors. No other products are available for these indications. Strategy: SP acquired a series of antagonists from Eli Lilly and Company that block the receptor subtype involved in aggression. These antagonists (LEAD SERIES) exhibit high affinity for the human receptor (<1.0 nM), are stable in stomach and blood, orally active, and pass into the brain. They require refinement to optimize these characteristics. The platform molecule has four essential structural zones that can be modified to improve bioavailability. Phase I objectives are (i) utilize combinatorial chemistry to modify structural zones on the LEAD SERIES to generate ca. 200 compounds, (ii) screen these for target receptor affinity and focus on those with Kds < 5 nM, (iii) test the high affinity compounds for in vitro biological activity, and (iv) test biologically active compounds for in vivo effects on an animal model of aggression. The findings will identify promising compounds for testing in Phase II for oral absorption, stability, CNS penetration, metabolism, and toxicity as well for efficacy in a primate model of self-injurious behavior. PROPOSED COMMERCIAL APPLICATION: SP will focus on the development of drugs to help in the control impulsivity, violence, and self-injurious behavior for the management of autism, Tourette' s syndrome, and mental retardation. It is estimated that more than 500,000 patients in the United States alone would have a need for these drugs. These drugs may also be used in the control of violence associated with mania, conduct disorder in a sub set of children with ADHD, and Alzheimer' s disease. There are no other products on the market for these indications.